The present application is related to Merck 18996, U.S. Ser. No. 08/059,038, filed May 7, 1993 now abandoned.
The present invention is concerned with a novel intermediate and process for synthesizing compounds which inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular certain oligopeptide analogs, such as compound J in the examples below. These compounds are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). These compounds are also useful for inhibiting renin and other proteases.
The invention described herein concerns the final bond-forming step in the synthesis of the HIV protease inhibitor J. In the invention, the penultimate intermediate 1 is converted to J via introduction of a 3-picolyl moiety in the form of 3-pyridinecarboxaldehyde 2 via a reductive alkylation. ##STR1##
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988) demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313,277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 35 1 (1987)]. The end product compounds, including certain oligopeptide analogs that can be made from the novel intermediates and processes of this invention, are inhibitors of HIV protease, and are disclosed in EPO 541,168, which published on May 12, 1993. See, for example, compound J therein.
Previously, the synthesis of Compound J and related compounds was accomplished via a 12-step procedure. This procedure is described in EPO 541,168. The last step in prior methods involved direct alkylation of the penultimate intermediate 1 with 3-picolyl chloride 3 to afford the HIV-protease inhibitor J. The disadvantage with this type of approach is the classical problem of overalkylation of amines with alkyl halides to form quaternary ammonium salts. In the present invention, overalkylation of the product J with 3-picolyl chloride, bromide or iodide results in the formation of the salt 4. Yield loss occurs. There are also difficulties in removing the salt 4, since multiple aqueous washes are required to effect complete removal. Complete removal of salt 4 by water washing is necessary. ##STR2##
The reductive alkylation of primary and secondary amines with carbonyl compounds is a classical reaction and is well documented in the literature [March, J. et al., in "Advanced Organic Chemistry", Third Edition, J. Wiley and Sons, New York, 1985, pp. 798-800]. The reductive alkylation of secondary amines by the use of aldehydes and NaCNBH.sub.3 [Borch, R. F. et al., J. Am. Chem. Soc., 1971, 93, 2897-2904] and NaH(OAc).sub.3 [Abdel-Mdgid, A. F. et al., Tetrahedron Lett., 1990, 31, 5595-5598] has been reported more recently in the literature.
The advantage of the reductive amination in this invention is avoiding the formation of overalkylation byproducts. Thus, the isolation procedure is simplified with this alkylation procedure. The yield loss is also avoided.
The starting material 3-pyridinecarboxaldehyde 2 is also a more desirable intermediate for large scale processing. The starting material has a lower molecular weight than 3-picolyl chloride 3 (hydrochloride), and as such is more cost effective on a kilogram basis. It is a more stable and a more easily handled intermediate and is not carcinogenic or irritating as 3, and on a commercial basis it is substantially less expensive than 3. The unexpected finding was that the penultimate intermediate I could be converted to the product J in high yield and good purity by this method without complication of the other functionalities present in the starting material 1 or the product J. For example, condensation with the amino indanol end group was not found as a side reaction.